α7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1

Abstract

Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the alpha7 nicotinic acetylcholine receptors (nAChRs). We hypothesized that schizophrenia-associated allelic variations within the NRG1 gene, via their effects on NRG1 isoform expression, would be associated with alterations in nAChR alpha7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5' region of the NRG1 gene on nAChR alpha7 mRNA transcript expression in both the dorsolateral prefrontal cortex (DLPFC) and hippocampus of normal controls and patients with schizophrenia using quantitative real-time PCR. NRG1 risk alleles at SNPs SNP8NRG221132 and rs6994992 predicted significantly lower nAChR alpha7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR alpha7 in the DLPFC. The genotype effect for rs6994992 and the haplotype effect were more pronounced within the schizophrenic patient group. To determine whether receptor levels follow that of mRNA expression, we performed receptor binding and autoradiography using [(125)I] alpha-bungarotoxin in the DLPFC. Consistent with the mRNA findings, we found a decrease in binding in risk allele carriers of SNP8NRG221132 as compared with heterozygous individuals. Together, these results suggest that the molecular mechanism of the association between NRG1 risk alleles and schizophrenia may include down-regulation of nAChR alpha7 expression.

Expression of GABA Signaling Molecules KCC2, NKCC1, and GAD1 in Cortical Development and Schizophrenia

“…Human brain specimens were processed, RNA was extracted, and quantitative RT-PCR (qRT-PCR) was performed using a paradigm described previously (Mathew et al, 2007). Species-specific probes and primer sets (Applied Biosystems) were used; for human NKCC1 (SLC12A2): Catalog No.…”

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

“…There is extensive evidence linking genetic alterations of α7-nAChR to schizophrenia and attentional deficits (18,19), including alterations at the transcription level (20). Recent data have also shown that α7-nAChR expression depends on neuregulin, another molecule linked to schizophrenia (21), and that smoking in schizophrenia may be a form of self-medication, normalizing expression of α7-nAChRs (22). More recent studies have linked α7-nAChRs to autism (23), attention deficit hyperactivity disorder [ADHD (24)], and AD (25), suggesting that a variety of dlPFC disorders are linked to alterations in α7-nAChR signaling.…”

The Role of Nitric Oxide and Nitrosative Stress in Schizophrenia

“…The cholinergic receptors (e.g., α7 nicotinic acetylcholine receptor) known to be sensitive to NO toxicity were decreased in both the blood and cortex of patients with schizophrenia (Mathew et al 2007 ). Some neuropsychological tests performed in patients with schizophrenia as well as in healthy controls indicated that nNOS was associated with functions of the prefrontal cortex, including cognition.…”